Malignant primary brain tumors are the most frequent cause of cancer death in children and young adults and account for more deaths than cancer of the kidney or melanoma. Moreover, current therapy is incapacitating and limited by non-specific toxicity. Despite hundreds of clinical trials, only a handful of agents have been approved for use in the clinic in the last century. As a result, current therapy for brain tumors represents the mos expensive medical therapy per quality-adjusted life-year saved currently provided in the US. Despite all of this, the tumors addressed in this application remain uniformly lethal. The Duke SPORE in Brain Cancer is an interdisciplinary research proposal that will use knowledge of brain tumor biology to develop diverse new approaches to the treatment of adult primary brain tumors in an expeditious fashion in order to have an immediate impact on cancer mortality and morbidity. In turn, this SPORE will determine the biological basis for observations made in these patient populations in order to improve these treatments. This application leverages a group of senior scientists and physician-scientists with a long history of collaboration and successful translational research to accomplish these goals through integration within the new Duke Cancer Institute and careful evaluation and monitoring of 4 Projects, 4 Cores and 2 Programs focused on attracting new and experienced investigators to this field. Project 1, led by John Sampson and Qi-Jing Li, will examine the impact of EGFRvIII-chimeric antigen T-cell receptor (CAR) therapy on tumor heterogeneity and whether miR-23a inhibition within EGFRvIII-CAR transduced T cells enhances cytotoxicity and confers resistance to host immunosuppression in the context of an IC delivered EGFRvIII- targeted CAR. Project 2, led by Hai Yan and John Sampson, will examine the safety of a peptide vaccine targeting the tumor-specific IDH1R132H mutation in formal preclinical toxicity studies and a pilot trial in patients with grade II or III IDHR132H positive glioma. Project 3, led by Michael Zalutsky and Darell Bigner, will evaluate the therapeutic potential of 211Atlabeled anti-tenascin MAb 81C6 in newly diagnosed GBM patients. Project 4, led by Matthias Gromeier and Allan Friedman, will conduct a clinical trial wit a promising oncolytic poliovirus and elucidate mechanisms by which this therapy generates an anti-tumor immune response. Each project will be evaluated frequently and replaced if not meeting its translational goals. The projects will be supported by 4 Cores that provide Administrative support (Core A); Biostatistics, Informatics, and Data Coordination resources (Core B); Clinical Trial Operations infrastructure (Core C), and Biospecimen, Pathology, and Immune Monitoring expertise (Core D). Collaborations within Duke, with other SPOREs, and government and non-government organizations will be emphasized to facilitate movement of SPORE research horizontally and vertically along the translational science continuum.